The present invention relates to a process for sulphonylating various nucleophiles, in particular nitrogenous nucleophiles. The invention relates more particularly to the sulphonylation of amines and more particularly anilines in the broad sense, i.e. amines linked to an aromatic ring.
The reaction is also directed towards a perhalosulphonylating reagent. Thus, the present invention relates more particularly to a sulphonylation reaction of an amine bearing an electron-withdrawing radical, especially when its amino functions are made soft, for example by the presence of an aryl radical (the amine then falling into the sub-category of anilines). The present invention is also directed towards the perhalosulphonylation of the very specific amine which is ammonia, to give either the amide or the imide.
The synthesis of these derivatives of sulphonamide type is often difficult, especially when the starting material used is a sulphonyl halide. Direct reactions usually fail, in particular with sulphonyl chlorides, especially when the organic part of the sulphonyls is highly electron-withdrawing, as is the case in particular when the atom bearing the sulphur of the sulphonyl function is perhalogenated, and more particularly when it is perfluorinated.
The explanation for these failures appears to be associated with the oxidizing nature of sulphonyl halides, in particular of trifluoromethanesulphonyl halides, which, like sulphuryl chloride, is an efficient oxidizing agent.
Accordingly, one of the aims of the present invention is to provide a process for obtaining sulphonamides of the above type using sulphonyl halides, in particular when these halides are heavy halides (i.e. halides corresponding to a halogen with an atomic number at least equal to that of chlorine).
It is preferred to use sulphonyl chlorides, for both economic and technical reasons. The technique has also been transposed to the synthesis of perfluorosulphonimides.
These aims and others which will become apparent hereinbelow are achieved by means of a sulphonylation process comprising a step of placing a nucleophile, whose nucleophilic atom is a nitrogen, in contact with a reagent comprising, for successive or simultaneous addition:
a heavy halide (i.e. a halide whose atomic number is at least equal to that of chlorine), of sulphonyl, advantageously sulphonyl chloride, and
an organic base comprising a trivalent atom from column V (the nitrogen column in the Mendeleev table), the lone pair of this atom being conjugated directly or indirectly to a bond linking two atoms, at least one of which is an atom from column V, and
by the fact that the organic part of the said sulphonyl is perhalogenated, advantageously perfluorinated, on the carbon borne by the sulphur.
The present invention is particularly advantageous for nucleophiles whose conjugate acid has a pKa of not more than about 7, advantageously not more than 6, preferably not more than 5, more preferably not more than 4. It is also advantageous for the oxidizable nucleophiles, and more generally when it is desired to use an oxidizable reagent.
The reason for this is that these nucleophiles are generally particularly difficult to sulphonylate. In particular, the invention is advantageous for nucleophiles whose nitrogen is linked to an electron-withdrawing group.
This electron-withdrawing group can be chosen in particular from aryls, advantageously electron-depleted aryls, and sulphonyls.
The said organic base comprising a trivalent atom from column V whose lone pair is conjugated to a bond can be used either as a base or as a catalyst for the reaction.
The reason for this is that the sulphonylation reaction releases a halohydric acid which salifies the nucleophile and makes the nucleophile more or less inert. Thus, it is desirable to add bases (in quantity and in nature) which will make it possible to release the nucleophile from the various acids present in the reaction medium such that it can act fully as a nucleophile.
The said organic base comprising a trivalent atom from column V conjugated to a bond is such that the said trivalent atom from column V is a trisubstituted atom and it forms a tertiary base.
According to one particularly advantageous embodiment of the present invention, the said bond linking two atoms is the bond of an imine function.
It is preferable for this imine function to be arranged such that the nitrogens are as far apart as possible, in other words such that the nitrogen of the imine function is that of the two atoms linked via the bond which is furthest from the trivalent atom from column V. That which has just been stated regarding the imine function is general for all the atoms from column V linked via the bond, when the bond comprises a carbon atom and an atom from column V.
According to the present invention, it is preferable for the organic base comprising a trivalent atom from column V, whose lone pair is conjugated to a bond, to have a sequence or skeleton of formula  greater than Nxe2x80x94(Cxe2x95x90C)nxe2x80x94Cxe2x95x90Nxe2x80x94 with n=0 or an integer chosen in the closed range (i.e. comprising the limits) 1 to 4, advantageously from 1 to 3, preferably from 1 to 2. Preferably, the above sequence corresponds to the formula  greater than Nxe2x80x94(C(R1)xe2x95x90C(R2))nxe2x80x94C(R3)xe2x95x90Nxe2x80x94 with n=0 or an integer chosen in the closed range (i.e. comprising the limits) 1 to 4, advantageously from 1 to 3, preferably from 1 to 2, and in which R1, R2 and R3, which may be identical or different, are chosen from hydrocarbon-based derivatives, advantageously alkyl derivatives containing not more than 4 carbon atoms, and hydrogen. Advantageously, according to the process, the said trivalent atom from column V forms or constitutes a tertiary amine.
More specifically, it is desirable for the said organic base comprising a trivalent atom from column V, whose lone pair is conjugated to a bond, to constitute a molecule of the following formula (R5)(R4)Nxe2x80x94(C(R1)xe2x95x90C(R2))nxe2x80x94Cxe2x95x90Nxe2x80x94R6 with n=0 or an integer chosen in the closed range (i.e. comprising the limits) 1 to 4, advantageously from 1 to 3, preferably from 1 to 2, and in which R1, R2 and R6, which may be identical or different, are chosen from hydrocarbon-based groups, advantageously alkyl groups containing not more than 4 carbon atoms, and hydrogen, and in which R4 and R5, which may be identical or different, are chosen from hydrocarbon-based groups, advantageously alkyl groups containing not more than 4 carbon atoms, one or two of the substituents R1, R2, R3, R4, R5 and R6 being able to be linked to other substituent(s) remaining to form one or more rings.
The observed catalytic effect is particularly pronounced when the said bond linking two atoms is endocyclic, especially when it is endocyclic in an aromatic ring. This is particularly the case for pyridine rings and rings derived therefrom such as quinoline or isoquinoline.
The organic base comprising a trivalent atom from column V whose lone pair is conjugated to a bond can advantageously be dialkylaminopyridines in particular in the para- or ortho-position (i.e. in position 2 or 4 of the pyridine); diazobicycloundecen (DBU)also gives an advantageous result.
Although the present invention can be used to form common sulphonimides, this reaction is particularly advantageous in the case of the formation of an amide or imide function starting with a nucleophilic substrate, in particular one consisting of an aniline, and more particularly when this aniline is linked to an electron-depleted aromatic ring.
This depletion can be correlated to the introduction of a hetero atom into the ring (in the case of 6-membered rings) or to the presence, on the ring bearing the aniline function to be sulphonylated, of substituent(s) which are electron-withdrawing overall.
In the case of an electronic depletion of a 6-membered ring by means of the introduction of a hetero atom, it should be pointed out that the substrate, or more specifically the substrates, can be autocatalytic, i.e. they may not require the presence of an amine according to the present invention.
As regards depletion by the substituents, it may be indicated as a guide that the invention is particularly suitable for treating arylamines in which the substituents, excluding the nucleophilic function to be sulphonylated, of the ring bearing the nucleophilic atom are such that the sum of their Hammett "sgr"p constants is at least equal to 0.14, advantageously to 0.20, preferably to 0.30.
When this sum of the Hammett constants reaches values of greater than 1, the reaction becomes particularly sluggish, and as such it is preferable for the sum of the Hammett constants for the ring bearing the amine function to be not more than 1, preferably not more than 0.9, more preferably not more than 0.7.
When the organic base comprising a trivalent atom from column V whose lone pair is conjugated, directly or indirectly, to a bond is used as catalyst (i.e. it is used in sub-stoichiometric amounts, more generally in an amount of between 1xc2x0/∞ and ⅕ of the stoichiometric amount, advantageously between {fraction (1/100)} and {fraction (1/10)} of the stoichiometric amount), it is then convenient to provide another base such that the reaction with respect to the nucleophilic substrate is as complete as possible.
In this case, the reagent used also comprises, for successive or simultaneous addition, an organic base, preferably one which cannot be alkylated. Non-alkylatable organic bases which may be chosen in particular are bulky dialkylphosphines, trialkylphosphines, phosphonium hydroxides, bulky dialkylamines, trialkylamines and ammonium hydroxides. The notion of bulkiness of bulky dialkylphosphines or dialkylamines such that they cannot be alkylated is well known to those skilled in the art.
In a great many cases, and in particular when solvents are used- it is preferable for the said non-alkylatable base to be liposoluble and to have at least one solubility in benzene which is significant (symbol xe2x80x9csxe2x80x9d in the xe2x80x9cHandbook of Chemistry and Physicsxe2x80x9d), and advantageously high (symbol xe2x80x9cvxe2x80x9d in the xe2x80x9cHandbook of Chemistry and Physicsxe2x80x9d).
As has been seen previously, it is usually desirable to carry out the placing in contact in an organic solvent. This solvent is advantageously relatively non-polar and preferably relatively immiscible with water. More particularly, it is desirable for not more than 10% by mass, advantageously not more than 5% and preferably not more than 2% by mass, to be miscible with water.
The amounts of base to be added and the amount of non-alkylatable base used during the reaction is advantageously at least equal to the amount required to neutralize the hydrohalic acid released.
In other words, the amount of base must be sufficient to ensure that the nucleophile is always present in free form (i.e. in true nucleophilic form) throughout the reaction.
The techniques towards which the present invention is directed are particularly suited to sulphonylation with perfluorinated alkylsulphonyl chlorides, which are perfluorinated in particular on the carbon borne by the sulphur.
The chloride which can most commonly be used is triflyl chloride (CF3SO2Cl). More generally, the organic part of the sulphonyl chloride corresponds to the formula (Rf).
Rf means a radical of formula:
EWGxe2x88x92(CX2)pxe2x88x92
in which the groups X, which may be identical or different, represent a chlorine, a fluorine or a radical of formula CnF2n+1 where n is an integer of not more than 5, preferably not more than 2, with the condition that at least one of the groups X is fluorine;
in which p represents an integer of not more than 2;
in which EWG represents an electron-withdrawing group whose possible functions are inert under the reaction conditions, advantageously fluorine or a perfluoro residue of formula CnF2n+1 with n being an integer of not more than 8, advantageously not more than 5.
The total number of carbons in Rf is advantageously between 1 and 15, preferably between 1 and 10.
The present invention is also directed towards a reagent which is useful for carrying out the process according to the invention. This reagent comprises, for successive or simultaneous addition:
a heavy halide (i.e. a halide whose atomic number is at least equal to that of chlorine), of sulphonyl, advantageously sulphonyl chloride, and:
an organic base comprising a trivalent atom from column V (the nitrogen column) whose lone pair is conjugated directly or indirectly to a xcfx80 bond linking two atoms, at least one of which is an atom from column V; the organic part of the said sulphonyl being perhalogenated, advantageously perfluorinated, on the carbon borne by the sulphur.
The reagent according to the present invention can also comprise, again for successive or simultaneous addition, a solvent. This solvent, including a mixture of solvents, is advantageously relatively non-polar and chosen from those which have low solubility in water. In certain cases, chlorinated aliphatic chains are not satisfactory.
As a touchstone for the polarity, it may be pointed out that the said relatively non-polar solvent is chosen from those, or mixtures of those, whose polarity (Eft expressed in kcal/mol) is not more than 40 (advantageously to two significant figures).
These relatively non-polar solvents are usually chosen from oxygenated organic compounds, in particular ethers, esters or even ketones, hydrocarbons, including petroleum fractions, and aromatic hydrocarbons which are generally halogenated. The latter solvents are particularly advantageous, in particular substituted benzenes and hydrocarbons which are halogenated on the ring.
That which has just been described above is particularly suitable for anilines, in particular those in which the said nitrogen atom is linked to a 6-membered aromatic ring, preferably a homocyclic ring, preferably a non-fused benzenic ring, are advantageously electron-depleted as has already been pointed out above. Overall, given the possible substituents, the process of the instant invention is particularly suited to amines linked to an aryl whose electron-richness is not more than that of a para-chlorophenyl (richness evaluated by means of the Hammett sigma "sgr"p constants).
Among the electron-withdrawing groups which are most commonly used, mention may be made of halogens (chlorine and fluorine), esters (of COxe2x80x94OR type), ketones, amides not liable to interfere with the sulphonylation, alkyls which are perhalogenated on the carbon linked directly to the ring, in particular alkyls which are perfluorinated on the atom next to the ring, nitrites, and groups containing a sulphone or phosphone function directly linked to the ring.
The technique is directed especially to the sulphonylation of anilines in the broad sense (i.e. amines borne by an aryl), but this teaching has also been transposed to the sulphonamidation of (aqueous) ammonia and the sulphimidation of sulphamides. The technique is also directed especially to the double sulphonylation of ammmonia to obtain directly the corresponding sulphimide.
In this case, the latter are advantageously in the form of a salt of a non-alkylatable organic base (it is the base which is non-alkylatable).
Under these conditions, the nitrogen bears a hydrogen or, more preferably, a negative charge (anion), whereas, in the case of anilines which has been targeted above, the aniline function comprises at least one hydrogen, preferably two, for reasons of steric hindrance.
The use of the said organic base comprising a trivalent atom from column V whose lone pair is conjugated to a xcfx80 bond makes it possible to carry out, in good yield, the double sulphonylation of nucleophiles which can be substituted twice (such as ammonia and primary amines). The preferred operating conditions are those described in the international patent application cited by reference and published by WIPO under the No. WO 98/52886, using, at least partially as base, the said organic base comprising a trivalent atom from column V whose lone pair is conjugated to a xcfx80 bond.
For reasons of work hygiene, chlorinated aliphatic derivatives are generally to be avoided, although they constitute a family of solvents which gives good results, even though it is not the family which gives the best performance, since their solubility, and in particular that of methylene chloride, is of the order of 2% by volume, i.e. 2.6% by weight.
As regards the solvents, solvents with a reducing nature should be avoided as much as possible.
The reaction can be carried out from xe2x88x9220 to about 200xc2x0 C., more generally from 0xc2x0 to about 100xc2x0 C.
It is easier to work at ambient temperature and pressure, but it is also possible to be at different, higher pressures. It is also possible to work in a closed chamber (such as an autoclave or sealed tube) and under autogenous pressure.
The non-limiting examples below illustrate the invention.